Reversible memory loss in a mouse model of Alzheimer's disease

Department of Neurology, University of Minnesota, Minneapolis 55455, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 09/2002; 22(15):6331-5.
Source: PubMed


Alzheimer's disease (AD) is a neurodegenerative condition, believed to be irreversible, characterized by inexorable deterioration of memory and intellect, with neuronal loss accompanying amyloid plaques and neurofibrillary tangles. In an amyloid precursor protein transgenic mouse model, Tg2576, little or no neuronal loss accompanies age-related memory impairment or the accumulation of Abeta, a 40-42 aa polypeptide found in plaques. Recently, we have shown inverse correlations between brain Abeta and memory in Tg2576 mice stratified by age (Westerman et al., 2002). Broadening the age range examined obscured this relationship, leading us to propose that small, soluble assemblies of Abeta disrupt cognitive function in these mice. Here we show that memory loss can be fully reversed in Tg2576 mice using intraperitoneally administered BAM-10, a monoclonal antibody recognizing the N terminus of Abeta. The beneficial effect of BAM-10 was not associated with a significant Abeta reduction, but instead eliminated the inverse relationship between brain Abeta and memory. We postulate that BAM-10 acts by neutralizing Abeta assemblies in the brain that impair cognitive function. Our results indicate that a substantial portion of memory loss in Tg2576 mice is not permanent. If these Abeta assemblies contribute significantly to memory loss in AD, then successfully targeting them might improve memory in some AD patients.

Download full-text


Available from: Takeshi Kawarabayashi
    • "Novel protocols and methods need to be established to provide reliable and valid detection of initial stages of p-preAD. In the light of the experience with Ab immunization (Balakrishnan et al., 2015; Bard et al., 2000; Clavaguera et al., 2009; Doody et al., 2014; Holmes et al., 2008; Iba et al., 2015; Kane et al., 2000; Kotilinek et al., 2002; Lannfelt et al., 2014; Meyer-Luehmann et al., 2006; Peeraer et al., 2015; Saido et al., 1995; Saido et al., 1996; Salloway et al., 2014; Schenk et al., 1999; Schilling et al., 2008; Stancu et al., 2015; Thal, Walter et al., 2015), I think that it will be essential to focus not only on preAD cases but also to take into account the stage of p-preAD pathology as well the proposed therapeutic mechanism to estimate whether a trial can be successful or not even when non-demented preAD cases are treated. In this respect, it is important to keep in mind that the currently available biomarkers for AD identify advanced p-preAD pathology when identifying non-demented individuals as preAD patients. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The current gold standard for the diagnosis of Alzheimer’s disease (AD) is the pathological examination at autopsy. Clinical diagnostic procedures are quite well developed for symptomatic AD and permit a reliable and valid identification of AD patients. Today, there is strong interest to diagnose AD already in a preclinical stage to include protective treatment strategies into the treatment regimes for AD. This is important because current therapies for AD mainly focus on symptomatic improvement rather than on delaying disease progression. The current diagnostic criteria for preclinical AD (preAD) rely on biomarker profiles indicative for AD in non-demented individuals. At autopsy, pathological lesions considered to represent AD pathology permit the classification of non-demented cases exhibiting AD pathology as pathologically-defined preAD (p-preAD) cases. Recent studies investigating amyloid imaging as a biomarker and comparing it with the post-mortem findings on AD pathology revealed that preAD cases identified clinically by amyloid imaging already exhibited advanced stages of AD pathology whereas p-preAD cases with initial AD lesions failed clinical detection. In this article I will discuss these findings and its potential impact on clinical studies aimed at stopping or delaying the progression from preAD to symptomatic AD as well as on the interpretation of imaging or biomarker data in relation to the underlying disease progress with a focus on propagation and maturation of Aβ and τ pathology in-p-preAD.
    No preview · Article · Jan 2016 · Neurology Psychiatry and Brain Research
  • Source
    • "In the past few years, different therapeutical approaches have been performed to modulate the amyloid brain depositions in APP-transgenic mice, including restricted administration of pharmaceutical agents [20], rich cholesterol diet [21], caloric diet [22], and intensive exercise [23]; however, Aí µí»½-based immunotherapy has been shown to be the most promising research field in reducing amyloid loads [24] [25] [26] [27] [28] and reversing memory deficits [9] [10] [29] in AD mouse models. Both active (Aí µí»½ peptides) and passive (Aí µí»½-specific antibodies) immunizations have been reported to achieve a certain degree of efficiency in reducing brain Aí µí»½ deposits in AD mouse models [30]. "

    Full-text · Dataset · Feb 2015
  • Source
    • "Implications for neural repair: A priority issue in contemporary neuroscience concerns the degree to which indigent repair mechanisms and neuroplasticity may reverse CNS damage after offending stimuli have dissipated. Evidence of spontaneous lesion reversibility, neuroplasticity and neurological recovery has been documented in APP transgenic mouse models of AD (Kotilinek et al., 2002), mutant tau-driven models of AD and frontotemporal dementia (Sydow et al., 2011), the MPTP mouse model of PD (Schmidt and Ferger, 2001), rodent models of Huntington disease (Yamamoto et al., 2000) and several spinocerebellar degeneration mimics (Boy et al., 2009). These remarkable reports suggest that clinically-relevant neuroregeneration may be invoked in a broad spectrum of neurodegenerative disorders following interruption of the salient pathological pathways. "

    Full-text · Article · Feb 2015 · Neural Regeneration Research
Show more